Hyaluronic acid (HA) is a naturally occurring mucopolysaccharide (also commonly referred to as glycosaminoglycan). It has been isolated by various methods from numerous tissue sources including vitreous humor, skin, synovial fluid, serum, chicken combs, shark skin, umbilical cords, tumors, hemolytic streptococci from pigskin, whale cartilage, and the walls of veins and arteries. HA may, however, also be synthesized artificially or made by recombinant technology. Moreover, it is known that HA may also be manufactured by fermentation of selected Streptococcus zooepidemicus bacterial strains (see U.S. Pat. No. 4,517,295 issued to Bracke et al.), and can readily be converted to its sodium salt. The repeating unit of the HA molecule is a disaccharide consisting of D-glucuronic acid and N-acetyl-D-glycosamine. Because HA has a negative charge at neutral pH, it is soluble in water, where it forms highly viscous solutions.
Fractions of HA, including its sodium salt, are known to form a stable polymer matrix when combined with a non-ionic polymer such as hydroxyethyl cellulose or hydroxypropyl cellulose. Such polymer matrix formulations are known to be useful in preparing compositions for various applications for human and animal use.
For example, a formulation containing sodium hyaluronate and hydroxyethylcellulose was formerly marketed under the name of Ionic Polymer Matrix (IPM) Wound Gel for applying to wounds to promote wound healing. In addition, polymer matrices of HA formulated with other active ingredients are known to be useful as topical drug formulations for delivering the active ingredients to sites below the dermal level of the skin. HA polymer matrix topical active ingredient formulations for trans-dermal delivery of active ingredients are disclosed for example in U.S. Pat. Nos. 5,897,880, 6,120,804, 6,387,407, and 6,723,345. HA polymer matrices formulated with other active ingredients are also known to be useful as formulations for sustained release of the pharmaceutical agents. HA polymer matrix formulations for sustained release delivery of active ingredients are disclosed in U.S. Pat. Nos. 6,063,405, 6,335,035, and 6,007,843.
Preparing sodium hyaluronate polymer matrix formulations presents many challenges. Initially, in the 1980s only HA obtained from animal sources was available commercially, and many of the formulations were delivered by injection, or used as drops in the eye, rather than for topical use for dermatological conditions. The natural HA used in various formulations has usually been obtained from rooster combs. The rooster comb (also known as a chicken comb) is an avian source and as such is of animal origin. As a result, sodium hyaluronate formulations manufactured using sodium hyaluronate from rooster combs have been known to cause allergies and carry other risks associated with products of animal origin, namely a risk of transmission of animal diseases to humans. Consequently, the currently approved topical products containing sodium hyaluronate formulations available on the market are contra-indicated for those patients who are hypersensitive to sodium hyaluronate of animal origin.
Moreover, sodium hyaluronate is difficult to formulate in high concentrations above 1.5% w/w, due to the difficulty in manufacturing a formulation that maintains stability and is not too viscous for normal use when packaged in a tube. For this reason many of the commercial formulations on the market have a concentration of HA or sodium hyaluronate well below 1% w/w, and many in fact have a concentration at around 0.2% w/w. To the inventors' knowledge, there are no products currently on the market that contain more than 1.5% w/w sodium hyaluronate. When not mixed and manufactured properly, a high HA or sodium hyaluronate concentration formulation will quickly break down, and therefore the percentage of HA or sodium hyaluronate in the formulation will fall below the acceptable limit (+/−10% of original amount), resulting in a very short shelf life for the product. Formulations containing a high concentration of sodium hyaluronate therefore present a challenge due to the instability of the matrix. This results in inconsistencies in the matrix formulation and impairs the ability of sodium hyaluronate formulations to perform their functions. For example, when applied to wounds to promote healing, a sodium hyaluronate polymer matrix formulation helps to maintain a moist wound environment, an effect that is dependent on the formulation maintaining its high level of sodium hyaluronate concentration. The maintenance of a moist wound environment is widely recognized to positively contribute to wound healing. However, due to their instability and the resulting drop in the level of sodium hyaluronate that occurs as the formulation breaks down, high concentration sodium hyaluronate formulations are not effective in maintaining a moist environment. When formulated for the delivery of a drug, the inconsistency of high concentration sodium hyaluronate formulations reduces the ability of such formulations to allow the drug to diffuse through the tissue when administered, thereby impairing their ability to achieve the therapeutic dose.
In addition, the sodium hyaluronate polymer matrix formulation product formerly marketed under the name of Ionic Polymer Matrix (IPM) Wound Gel was withdrawn from the market due to problems with the formulation.
Therefore, a need exists for a method for formulating a sodium hyaluronate polymer matrix containing a high concentration of sodium hyaluronate that can be manufactured and sold commercially.